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1.
Dopamine-Decorated TiO2 Nanoparticles in Water: A QM/MM vs an MM Description.
Siani, P, Motta, S, Ferraro, L, Dohn, AO, Di Valentin, C
Journal of chemical theory and computation. 2020;(10):6560-6574
Abstract
Nanoparticle functionalization is a modern strategy in nanotechnology to build up devices for several applications. Modeling fully decorated metal oxide nanoparticles of realistic size (few nanometers) in an aqueous environment is a challenging task. In this work, we present a case study relevant for solar-light exploitation and for biomedical applications, i.e., a dopamine-functionalized TiO2 nanoparticle (1700 atoms) in bulk water, for which we have performed an extensive comparative investigation with both MM and QM/MM approaches of the structural properties and of the conformational dynamics. We have used a combined multiscale protocol for a more efficient exploration of the complex conformational space. On the basis of the results of this study and of some QM and experimental data, we have defined strengths and limitations of the existing force field parameters. Our findings will be useful for an improved modeling and simulation of many other similar hybrid bioinorganic nanosystems in an aqueous environment that are pivotal in a broad range of nanotechnological applications.
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2.
The Principle of Nanomaterials Based Surface Plasmon Resonance Biosensors and Its Potential for Dopamine Detection.
Kamal Eddin, FB, Fen, YW
Molecules (Basel, Switzerland). 2020;(12)
Abstract
For a healthy life, the human biological system should work in order. Scheduled lifestyle and lack of nutrients usually lead to fluctuations in the biological entities levels such as neurotransmitters (NTs), proteins, and hormones, which in turns put the human health in risk. Dopamine (DA) is an extremely important catecholamine NT distributed in the central nervous system. Its level in the body controls the function of human metabolism, central nervous, renal, hormonal, and cardiovascular systems. It is closely related to the major domains of human cognition, feeling, and human desires, as well as learning. Several neurological disorders such as schizophrenia and Parkinson's disease are related to the extreme abnormalities in DA levels. Therefore, the development of an accurate, effective, and highly sensitive method for rapid determination of DA concentrations is desired. Up to now, different methods have been reported for DA detection such as electrochemical strategies, high-performance liquid chromatography, colorimetry, and capillary electrophoresis mass spectrometry. However, most of them have some limitations. Surface plasmon resonance (SPR) spectroscopy was widely used in biosensing. However, its use to detect NTs is still growing and has fascinated impressive attention of the scientific community. The focus in this concise review paper will be on the principle of SPR sensors and its operation mechanism, the factors that affect the sensor performance. The efficiency of SPR biosensors to detect several clinically related analytes will be mentioned. DA functions in the human body will be explained. Additionally, this review will cover the incorporation of nanomaterials into SPR biosensors and its potential for DA sensing with mention to its advantages and disadvantages.
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3.
The "Sick-but-not-Dead" Phenomenon Applied to Catecholamine Deficiency in Neurodegenerative Diseases.
Goldstein, DS
Seminars in neurology. 2020;(5):502-514
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Abstract
The catecholamines dopamine and norepinephrine are key central neurotransmitters that participate in many neurobehavioral processes and disease states. Norepinephrine is also the main neurotransmitter mediating regulation of the circulation by the sympathetic nervous system. Several neurodegenerative disorders feature catecholamine deficiency. The most common is Parkinson's disease (PD), in which putamen dopamine content is drastically reduced. PD also entails severely decreased myocardial norepinephrine content, a feature that characterizes two other Lewy body diseases-pure autonomic failure and dementia with Lewy bodies. It is widely presumed that tissue catecholamine depletion in these conditions results directly from loss of catecholaminergic neurons; however, as highlighted in this review, there are also important functional abnormalities in extant residual catecholaminergic neurons. We refer to this as the "sick-but-not-dead" phenomenon. The malfunctions include diminished dopamine biosynthesis via tyrosine hydroxylase (TH) and L-aromatic-amino-acid decarboxylase (LAAAD), inefficient vesicular sequestration of cytoplasmic catecholamines, and attenuated neuronal reuptake via cell membrane catecholamine transporters. A unifying explanation for catecholaminergic neurodegeneration is autotoxicity exerted by 3,4-dihydroxyphenylacetaldehyde (DOPAL), an obligate intermediate in cytoplasmic dopamine metabolism. In PD, putamen DOPAL is built up with respect to dopamine, associated with a vesicular storage defect and decreased aldehyde dehydrogenase activity. Probably via spontaneous oxidation, DOPAL potently oligomerizes and forms quinone-protein adducts with ("quinonizes") α-synuclein (AS), a major constituent in Lewy bodies, and DOPAL-induced AS oligomers impede vesicular storage. DOPAL also quinonizes numerous intracellular proteins and inhibits enzymatic activities of TH and LAAAD. Treatments targeting DOPAL formation and oxidation therefore might rescue sick-but-not-dead catecholaminergic neurons in Lewy body diseases.
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Altered dopamine signalling in chronic epigastric pain syndrome.
Chojnacki, C, Poplawski, T, Blasiak, J, Fila, M, Konrad, P, Chojnacki, J
Journal of physiology and pharmacology : an official journal of the Polish Physiological Society. 2020;(6)
Abstract
Chronic epigastric pain syndrome (CEPS) is an important diagnostic problem, especially in patients without macroscopic and microscopic changes in gastric mucosa. The cause of this ailment is unclear. The aim of this study was the assessment of coexistence between symptoms of this syndrome and secretion level of dopamine (DA), as well as the efficacy of peripheral and central D2 receptors antagonist. Sixty depressive patients with CEPS occurring independently of the diet and with no Helicobacter pylori infection and 30 healthy subjects were enrolled in this study. Plasma DA and urinary homovanilic acid (HVA) concentration were measured by ELISA, and the mRNA expression of dopa decarboxylase (DDC) in gastric mucosa was evaluated by RT-PCR in 30 patients with CEPS and 30 controls. Severity of epigastric pain before and after 12 weeks 2 x 50 mg itopride or sulpiride treatment was evaluated using the modified 10-point Visual Analogue Scale. Higher average levels of plasma DA and urinary HVA levels in CEPS patients than controls 129.5 ± 22.0 versus 109.1 ± 18.4 pg/ml (p < 0.001) and 6.82 ± 1.55 versus 5.39 ± 1.04 mg/24 h, respectively were obtained. Moreover, the expression of DDC in gastric mucosa of CEPS patients was higher than in healthy subjects (p < 0.01). Sulpiride subsided epigastric pain in 73.3%, but itopride reduced it only in 6.6% of CEPS patients. We concluded that altered dopamine signalling may affect locally-and-centrally mediated chronic epigastric pain.
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5.
Putative COVID- 19 Induction of Reward Deficiency Syndrome (RDS) and Associated Behavioral Addictions with Potential Concomitant Dopamine Depletion: Is COVID-19 Social Distancing a Double Edged Sword?
Blum, K, Cadet, JL, Baron, D, Badgaiyan, RD, Brewer, R, Modestino, EJ, Gold, MS
Substance use & misuse. 2020;(14):2438-2442
Abstract
The overwhelming fatalities of the global COVID-19 Pandemic will have daunting epigenetic sequala that can translate into an array of mental health issues, including panic, phobia, health anxiety, sleep disturbances to dissociative like symptoms including suicide. Method: We searched PUBMED for articles listed using the search terms "COVID 19 Pandemic", COVID19 and genes," "stress and COVID 19", Stress and Social distancing: Results: Long-term social distancing may be neurologically harmful, the consequence of epigenetic insults to the gene encoding the primary receptor for SARS-CoV2, and COVID 19. The gene is Angiotensin I Converting-Enzyme 2 (ACE2). According to the multi-experiment matrix (MEM), the gene exhibiting the most statistically significant co-expression link to ACE2 is Dopa Decarboxylase (DDC). DDC is a crucial enzyme that participates in the synthesis of both dopamine and serotonin. SARS-CoV2-induced downregulation of ACE2 expression might reduce dopamine and serotonin synthesis, causing hypodopaminergia. Discussion: Indeed, added to the known reduced dopamine function during periods of stress, including social distancing the consequence being both genetic and epigenetic vulnerability to all Reward Deficiency Syndrome (RDS) addictive behaviors. Stress seen in PTSD can generate downstream alterations in immune functions by reducing methylation levels of immune-related genes. Conclusion: Mitigation of these effects by identifying subjects at risk and promoting dopaminergic homeostasis to help regulate stress-relative hypodopaminergia, attenuate fears, and prevent subsequent unwanted drug and non-drug RDS type addictive behaviors seems prudent.
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Substrate-induced conformational dynamics of the dopamine transporter.
Nielsen, AK, Möller, IR, Wang, Y, Rasmussen, SGF, Lindorff-Larsen, K, Rand, KD, Loland, CJ
Nature communications. 2019;(1):2714
Abstract
The dopamine transporter is a member of the neurotransmitter:sodium symporters (NSSs), which are responsible for termination of neurotransmission through Na+-driven reuptake of neurotransmitter from the extracellular space. Experimental evidence elucidating the coordinated conformational rearrangements related to the transport mechanism has so far been limited. Here we probe the global Na+- and dopamine-induced conformational dynamics of the wild-type Drosophila melanogaster dopamine transporter using hydrogen-deuterium exchange mass spectrometry. We identify Na+- and dopamine-induced changes in specific regions of the transporter, suggesting their involvement in protein conformational transitions. Furthermore, we detect ligand-dependent slow cooperative fluctuations of helical stretches in several domains of the transporter, which could be a molecular mechanism that assists in the transporter function. Our results provide a framework for understanding the molecular mechanism underlying the function of NSSs by revealing detailed insight into the state-dependent conformational changes associated with the alternating access model of the dopamine transporter.
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7.
Enhancement in dopamine reduces generous behaviour in women.
Oroz Artigas, S, Liu, L, Strang, S, Burrasch, C, Hermsteiner, A, Münte, TF, Park, SQ
PloS one. 2019;(12):e0226893
Abstract
Generosity is a human behavior common in social contexts. However, humans are not equally generous to everyone alike. Instead, generosity decreases as a function of social distance, an effect called social discounting. Studies show that such social discounting effect depends on diverse factors including personality traits, cultures, stress or hormonal levels. Recently, the importance of the neurotransmitter dopamine in regulating social interactions has been highlighted. However, it remains unclear how exactly dopamine agonist administration modulates generous behavior as a function of social discounting. Here, we investigate the causal effect of dopamine agonist administration on social discounting in a pharmacological intervention study. We employ a randomized, double-blind, within-subject design to investigate the impact of the D2/D3 receptor agonist pramipexole on social discounting by keeping gender constant. We apply hyperbolic social discount model to the data and provide evidence that women under pramipexole become less generous in general, especially towards close others. Our results highlight the crucial role of dopamine in social decision making.
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8.
Dopamine Cytotoxicity on SH-SY5Y Cells: Involvement of α-Synuclein and Relevance in the Neurodegeneration of Sporadic Parkinson's Disease.
Ganguly, U, Ganguly, A, Sen, O, Ganguly, G, Cappai, R, Sahoo, A, Chakrabarti, S
Neurotoxicity research. 2019;(4):898-907
Abstract
The cytotoxicity of dopamine on cultured cells of neural origin has been used as a tool to explore the mechanisms of dopaminergic neurodegeneration in Parkinson's disease. In the current study, we have shown that dopamine induces a dose-dependent (10-40 μM) and time-dependent (up to 96 h) loss of cell viability associated with mitochondrial dysfunction and increased intra-cellular accumulation of α-synuclein in cultured SH-SY5Y cells. Dopamine-induced mitochondrial dysfunction and the loss of cell viability under our experimental conditions could be prevented by cyclosporine, a blocker of mitochondrial permeability transition pore, as well as the antioxidant N-acetylcysteine. Interestingly, the dopamine effects on cell viability and mitochondrial functions were significantly prevented by knocking down α-synuclein expression by specific siRNA. Our results suggest that dopamine cytotoxicity is mediated by α-synuclein acting on the mitochondria and impairing its bioenergetic functions.
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Resting-state dynamics as a neuromarker of dopamine administration in healthy female adults.
Bellucci, G, Münte, TF, Park, SQ
Journal of psychopharmacology (Oxford, England). 2019;(8):955-964
Abstract
BACKGROUND Different neuromarkers of people's emotions, personality traits and behavioural performance have recently been identified. However, not much attention has been devoted to neuromarkers of neural responsiveness to drug administration. AIMS We investigated the predictive neuromarkers of acute dopamine (DA) administration. METHODS In a double-blind, within-subject study, we administrated a DA agonist (pramipexole) or placebo to 27 healthy female subjects. Using multivariate classification and prediction analyses, we examined whether dopaminergic modulations of task-free resting-state brain dynamics predict individual differences in pramipexole's modulation of facial attractiveness evaluations. RESULTS Our results demonstrate that pramipexole's effects on brain dynamics could be successfully discriminated from resting-state functional connectivity (accuracy: 78.9%; p < 0.0001). On the behavioural level, pramipexole increased facial attractiveness evaluations (t(39) = 4.44; p < 0.0001). In particular, pramipexole administration enhanced connectivity strength of the cinguloopercular network (t(23) = 3.29; p = 0.003) and increased brain signal variability in subcortical and prefrontal brain areas (t(13) = 3.05, p = 0.009). Importantly, multivariate predictive models reveal that pramipexole-dependent modulation of resting-state dynamics predicted the increase of facial attractiveness evaluations after pramipexole (connectivity strength: standardized mean squared error, smse = 0.65; p = 0.0007; brain signal variability: smse = 0.94, p = 0.015). CONCLUSION These results demonstrate that modulations of resting-state brain dynamics induced by a DA agonist predict drug-related effects on evaluation processes, providing a neuromarker of the neural responsiveness of specific brain networks to DA administration.
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10.
Presynaptic Striatal Dopaminergic Function in Atypical Parkinsonism: A Metaanalysis of Imaging Studies.
Kaasinen, V, Kankare, T, Joutsa, J, Vahlberg, T
Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2019;(12):1757-1763
Abstract
Multiple-system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS) have signs and symptoms overlapping those of Parkinson disease (PD), complicating their clinical diagnosis. Although presynaptic dopaminergic brain imaging with PET and SPECT is clinically widely used for patients with suspected PD, the benefit of functional imaging in atypical parkinsonism syndromes remains unclear. We compared striatal presynaptic dopaminergic function in MSA parkinsonism variant (MSA-P), MSA cerebellar variant (MSA-C), PSP, CBS, and PD using combined quantitative data from all published studies. Methods: The PubMed database was searched from inception to August 2018 for the terms "dopamine" OR "dopaminergic" AND "PET" OR "SPECT" OR "SPET" and keywords related to PD, MSA, PSP, and CBS. In total, 1,711 publications were identified. PET or SPECT studies comparing patients with atypical parkinsonism to another diagnostic group (PD, MSA, PSP, or CBS) were included. Tracers for dopamine transporter (DAT), aromatic amino acid decarboxylase (AADC), or vesicular monoamine type 2 were investigated. Tracer binding data were extracted from the original articles. Heterogeneity of the data was examined using I2 statistics, and a random-effects model was used to summarize data. Hedges g was used as an estimator of effect size in group comparisons. Results are reported according to PRISMA guidelines. Results: Thirty-five studies (29 DAT, 6 AADC, no vesicular monoamine type 2 studies) with 356 MSA-P patients, 204 PSP patients, 79 CBS patients, and 62 MSA-C patients were included in the metaanalysis. Caudate nucleus and putamen DAT function was clearly lower in PSP than in PD (caudate: 34.1% difference, g = -1.08, 95% confidence interval [CI] = -1.52 to -0.64; putamen: 18.2%, g = -0.86, 95% CI = -1.50 to -0.21) and MSA-P (striatum: 31.4%, g = -0.70, 95% CI = -1.21 to -0.19) and was clearly lower in MSA-P than in MSA-C (striatum: 46.0%, g = 1.46, 95% CI = 0.23 to 2.68). Although not significant because of limited data, aromatic l-AADC results paralleled the DAT findings. Conclusion: Striatal presynaptic DAT function is clearly lower in PSP patients than in PD and MSA-P patients and is clearly lower in MSA-P patients than in MSA-C patients.